Prostate cancer is the second most common malignancy in men and is the third most common cause of cancer death in men older than age 55. Harrison""s Principles of Internal Medicine, Eds. J. D. Wilson et al., 11th Edition, pp. 1630-1633, McGraw Hill, New York, 1991. New methods of identifying and treating prostate cancer early are extremely important in saving the lives of those afflicted. Presently, only a limited number of treatments are available for treatment of prostate cancer. These treatments include surgery, radiation therapy, and androgen deprivation.
There is a need for additional methods of treatment of prostate cancer.
The present invention relates to a method of delivering a drug to a specific cell type, such as a cancer cell, in an individual by means of a drug complex which comprises three components and is also the subject of the present invention. The three components of the drug complex include the following: a targeting carrier molecule; a linker which is acted upon by a molecule present at an effective concentration in the environs of the specific cell (referred to as a target cell); and a drug (or agent) to be delivered to the specific cell type. The targeting carrier molecule is one which is delivered specifically to (has a biodistribution which favors) a specific cell type, or tissue containing the specific cell type, to which the drug is to be delivered. The linker can be any type of molecule such as a peptide, provided that it is a substrate for a molecule, such as an enzyme (e.g., a protease), which is found in the environs of the target cell to which the drug is to be delivered and is present in sufficient quantities at the site(s) of the target cell to act upon the linker and release the drug or agent to be delivered, such as by cleaving the linker. The linker can comprise more than one type of molecule. For example, the linker can comprise a component which is a substrate for a molecule which acts upon it and releases the drug to be delivered and an additional component(s), such as a molecule which acts as a good leaving group; additional amino acid residues or other molecule, such as one which acts as a spacer between the targeting carrier molecule and the drug to be delivered. The drug or agent to be delivered can be any therapeutically or diagnostically useful drug or agent, such as a cytotoxic drug or an imaging agent. It remains essentially functionally inactive while it is a component of the drug complex; upon release at the site(s) of the target cells, the drug is functionally active (exerts or displays its therapeutic or diagnostic function(s)). In one embodiment, the linker comprises a substrate for a molecule as described previously, and one or more other additional components, such as chemical molecules, e.g. para-amino benzoic acid (pABA) and para-aminobenzyloxycarbonyl (pABOC), which are good leaving groups. Optionally, there can be amino acid residues in addition to those acted upon by the enzyme or other molecule. Such amino acid residues can be at either or both ends (amino and/or carboxy terminus) of the amino acid residues acted upon. In one embodiment, additional amino acid residue (or residues) is/are included between the carboxy terminal amino acid of the substrate and the drug or agent to be delivered. Cleavage of the substrate results in a product in which an amino acid residue(s) is attached to the drug or agent delivered to the target cell. Such amino acid residues can be, for example, one or more amino acid residues of the substrate (e.g., if the enzyme cleaves at an internal amino acid residue in the substrate), one or more amino acid residues which are not substrate amino acid residues (e.g., if the enzyme cleaves between the carboxyl terminal amino acid residue of the substrate and the amino terminal amino acid residue of additional amino acids) or both. The additional amino acid residue(s) between the substrate carboxyl terminal amino acid residue and the drug or agent to be delivered to the target cell can be linked to the drug or agent in such a manner (e.g., through an amide bond, disulfide bond or ester bond) that cellular enzymes act upon them; resulting in release of the amino acid residue(s) attached to the drug or agent when it enters the cell. The drug or agent to be delivered can be any therapeutically or diagnostically useful drug or agent, such as a cytotoxic drug or an imaging agent.
The present invention also relates to a method of delivering a drug to a specific cell type by means of the drug complex described herein. In the method, the drug complex is administered to an individual in need of therapy or in whom a diagnostic procedure or assessment is to be conducted.
In one embodiment, the present invention is a method of killing prostate cancer cells, including metastatic prostate cancer cells or androgen independent prostate cancer cells, in a man with prostate cancer. The method is particularly effective because it makes use of a drug complex whose components provide the basis for localization to and killing prostate cancer cells, particularly androgen-independent cancer cells. The method of killing metastatic prostate cancer cells comprises administering to the man a therapeutically effective amount of a drug complex which comprises three components: a targeting carrier molecule which is selectively delivered to prostate tissue, bone or both; a linker which comprises a component acted upon by prostate specific antigen (PSA) which is present in the microenvironment of malignant prostatic epithelial cells; and a cytotoxic drug which is toxic to prostatic cancer cells. The present invention also relates to a method of treating metastatic cancer in an individual, in which the drug complex described above is administered to a man with prostate cancer, in a quantity sufficient to deliver the cytotoxic drug to prostate cancer cells at a concentration sufficient to kill some or all of the cancer cells or inhibit replication or division of the cancer cells. Drug complexes useful in the method of treating prostate cancer and the method of killing prostate cancer cells (such as androgen independent cells) are also the subject of this invention.
In a further embodiment, the drug complex comprises a targeting carrier molecule which is an imaging agent for prostate and prostate derived tumors, such as fluoropropylputrescine (e.g., N-3 fluoropropylputrescine); a peptide which serves as a linker and comprises amino acid residues acted upon by PSA; and a cytotoxic drug, which is linked to the targeting carrier molecule by the peptide. The linker can be comprised of more than one type of molecule, as described herein. The drug complex is administered to an individual by any route which results in delivery of the cytotoxic drug to prostate cells. In one embodiment, the drug complex is administered intravenously.
Combining a targeting carrier molecule with specificity for prostate tissue, bone or both with a cytotoxic drug, which are joined by a linking peptide that is a substrate for PSA, provides a treatment for cancer having higher efficacy and lower toxicity than presently available treatments.